The present invention relates to pharmaceutical compositions and methods for treating demyelinating diseases. In particular, the invention relates to treatment using agents which inhibit leukocyte adhesion mediated by lymphocyte homing receptors (LHR).
Recent work has established that specialized cell surface receptors (termed here selectins or LEC-CAMs) on endothelial cells and various circulating cells are involved in a number of intercellular interactions. LHR (also known as gp90.sup.MEL, gp100.sup.MEL, gp110.sup.MEL, Mel-14 antigen, Leu8 antigen, TQ1 antigen, DREG antigen, LAM-1, selectin 1, LECAM-1 and LEC-CAM-1) is a selectin receptor on the surface of leukocytes and is known to be involved in the adhesive interactions of leukocytes with the endothelial lining of blood vessels. This adhesive interaction is a prerequisite for the movement of leukocytes from the blood to tissue sites where immune reactions and inflammatory reactions occur. LHR is also important for lymphocyte homing from the blood into secondary lymphoid organs.
All selectins share certain structural features, including a lectin-like region which recognizes specific carbohydrate-containing ligands. For a review, of selectin receptors see, Springer, Nature, 346:425 (1990), which is incorporated herein by reference. Other selectin receptors are found on endothelial cells and platelets. Endothelial leukocyte adhesion molecule-1 (ELAM-1) is present on endothelial cells and is involved in the recognition of various circulating cells by the endothelium. Granule membrane protein-140 (GMP-140) is present on the surface of platelets and endothelial cells, where it mediates platelet-leukocyte and endothelium-leukocyte interactions.
There is currently an interest in developing highly specific competitive inhibitors of selectin-mediated cellular adhesion. Such inhibitors are useful in therapeutic regimens to treat various selectin-mediated disease responses. In particular, little is known about the role selectins might play in responses other than inflammation and lymphocyte homing. Identification of other interactions involving selectin receptors will open new paths to therapy for other disease processes.